There is controversy regarding which currently available therapeutic intervention offers the greatest benefit for treatment of membranous lupus nephropathy. In the present study, the efficacy and toxicity of three immunosuppressive drug regimens will be evaluated. Detailed tests of renal function (glomerular filtration and renal plasma flow rates), glomerular permselectivity (using fractional clearance of graded dextrans) and kidney biopsy morphology will be performed at the beginning and end of treatment. Patients with systemic lupus, more than 2 grams per day of proteinuria and biopsy documented membranous nephropathy will be randomized to receive: a) alternate day prednisone alone (control group), b) alternate day prednisone plus intravenous pulse cyclophosphamide up to 1.0 gram per square meter body surface area every other month for 6 total doses, or c) alternate day prednisone plus oral cyclosporin A up to 200 mg per square meter body surface area daily. Lupus disease activity, renal function tests and drug toxicities will be monitored closely. Analysis will include comparison of the numbers of favorable outcomes of glomerular filtration rate, renal plasma flow, permselectivity, glomerular pathology and drug-related toxicities appearing in each treatment group. Forty one patients have entered the study. Randomization assigned 26 patients to prednisone plus immunosuppressive drugs and 15 patients to prednisone alone (controls). At the end of one year of planned protocol treatment, the percentage of patients achieving complete remission (proteinuria less than 0.3 g/d) and those with persistent nephrotic proteinuria (greater than 3.5 g/d) were analyzed. Significantly more favorable outcomes were seen with combined prednisone and immunosuppressive drugs than with prednisone alone. There were no differences in rates of achieving complete remission with either adjunctive cyclosporine (n equal 12) or cyclophosphamide (n equal 14). Of the patients who achieved at least partial remission of proteinuria (less than 2 g/d) and who were observed for more than one additional year of follow-up to assess the risk of relapse of nephrotic range proteinuria, there was a trend toward more frequent relapses after finishing cyclosporine (5 of 8 patients) than after cyclophosphamide treatment (1 of 8 patients) (Fisher exact test, P equal 0.06). On average, no significant change in glomerular filtration rate has been observed in the three treatment groups.